Medicaments for slowing parkinson&#39;s disease

ABSTRACT

Opicapone, levodopa and an AADC inhibitor are described for use in slowing the progression of Parkinson&#39;s Disease.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. application Ser.No. 15/528,886, filed May 23, 2017, which is U.S. national stage filingunder 35 U.S.C. § 371(c), of International Application No.PCT/162015/000766, filed May 27, 2015, which claims foreign priority ofInternational Application No. PCT/162014/003241, filed Nov. 28, 2014.The entire contents of each of the aforementioned applications areincorporated herein by reference.

FIELD OF INVENTION

The present invention relates to the use of medicaments to slow theprogression of Parkinson's Disease (PD). More particularly, thisinvention relates to the use of opicapone and levodopa (L-DOPA)optionally together with an amino acid decarboxylase inhibitor (AADCinhibitor, AADCi) to slow the progression of PD.

BACKGROUND OF THE INVENTION

PD is characterised by loss of dopamine-generating cells in a region ofthe brain known as the substantia nigra. Treatment of PD thereforefocuses on increasing dopamine levels in the brain, and the variousdopaminergic drugs used in PD treatment aim to either replace dopamineor prevent its degradation.

A number of PD symptoms arise from decreased dopamine levels, and can beclassified into motor and non-motor symptoms. The group of motorsymptoms include i) resting tremor that affects, for example the arms,legs and jaw; ii) a slowness of movement or bradykinesia, and iii) lackof movement/rigidity or akinesia. In addition, the motor symptomsexperienced by PD sufferers also include problems with posture(instability thereof) and gait.

Non-motor symptoms of PD patients include neuropsychiatric symptoms,sleep disorders and wakefulness, and autonomic symptoms.

PD is a heterogeneous disorder with a clinical presentation that variessubstantially from patient to patient. Current clinical guidelines (EMA2012 guideline (EMA/CHMP/330418/2012 rev. 2) provide that the clinicaldiagnosis of PD requires bradykinesia and at least one of the following:resting tremor, muscular rigidity and postural reflex impairment (coresymptoms).

PD is characteristically a progressive neurodegenerative disorder. Theprogress of the disease is apparent from the response of the PD patientto dopaminergic therapy over time. In the initial stages of the diseasethe principal symptoms such as tremor, bradykinesia, and rigidity canusually be ameliorated by dopaminergic therapies such as dopamineagonists, monoamine oxidase inhibitors or levodopa. None of theseconventional treatments are considered to slow the progression of PD butcan help patients control at least some motor symptoms. PD patients aresaid to be in the ON state when they are free, or largely free, of thePD symptoms described above. In contrast, PD patients are said to be inthe OFF state when they are not in the ON state, for example when theyexhibit PD symptoms.

The symptoms of PD may be ameliorated by treatment with dopamineagonists, monoamine oxidase inhibitors or levodopa. None of theseconventional treatments are considered to slow the progression of PD butall can help at least some patients control the symptoms of the disease,such as tremor.

After this initial disease stage, the efficacy of the dopaminergictherapy reduces and “wearing off” or “end of dose” deterioration (suchas motor fluctuations) occurs in most patients, as well as dyskinesia(the phenomenon of drug-induced involuntary movements including choreaand dystonia). Motor fluctuations refer to a situation where thepatients fluctuate between being in the ON state and the OFF state, witha tendency, as the PD progresses, to have an increase in time of beingin the OFF state (‘OFF time’) and a decrease in time of being in the ONstate (‘ON time’). These can be dose-dependent and more predictable, ornon-dose-dependent.

Because the effectiveness of levodopa can appear to decrease over longerperiods of time, certain physicians prefer to commence treatment of PDwith a dopamine agonist and/or monoamine oxidase inhibitor, reservingtreatment with levodopa until later in the treatment sequence.

Levodopa is normally used together with an AADC inhibitor such ascarbidopa or benserazide in order to reduce its peripheral metabolismand so reduce the dose required. It may also be used together with aCOMT inhibitor, such as entacapone, to further reduce its peripheralmetabolism and so further reduce the dose of levodopa required.

When evaluating the efficacy of known and candidate therapies forParkinson's disease treated patients can be referred to as being in theON or OFF states. Therapeutic benefit is thus established by an increasein ON time and/or a reduction in OFF time. An increase in ON timeprovides an increased duration of relief from symptoms. A decrease inOFF time provides for reduced periods of time in which PD patientsundergoing therapy exhibit PD symptoms. Measure of ON and OFF time areconventionally established by observation, with the patient and/orphysician keeping a diary of symptoms and their timings. The observed ONand OFF times in a treatment group can be compared with those inalternative treatment or placebo treated groups as appropriate to theclinical context. Methods used for these evaluations include the UnifiedParkinson's Disease Rating Scale or UPDRS (see Fahn S. UnifiedParkinson's disease rating scale. In Fahn S, Marsden C D, Goldstein M,and Calne D B (eds) Recent Developments in Parkinson's Disease.McMillan, 1987, New York) to follow the longitudinal course of PD andthe MDS (Movement Disorder Society)-UPDRS (see Goetz, et al (1 Jan.2007). “Movement Disorder Society-sponsored revision of the UnifiedParkinson's Disease Rating Scale (MDS-UPDRS): Process, format, andclinimetric testing plan”. Movement Disorders 22 (1): 41-47). As knownto those skilled in the art various other approaches can be used asdeemed appropriate to establish clinical response, non-limiting examplesof the approaches that might be applicable are PDQ-39 (Jenkinson et al,The Parkinson's disease questionnaire. User manual for the PDQ-39, PDQ-8and PDQ Summary Index. Oxford: Health Services Research Unit, Departmentof Public Health, University of Oxford, 1998), NMSS (Chaudhuri et al.,“The metric properties of a novel non-motor symptoms scale forParkinson's disease: results from an international pilot study,”Movement Disorders, vol. 22, no. 13, pp. 1901-1911, 2007), PDSS(Chaudhuri et al. The Parkinson's disease sleep scale: A new instrumentfor assessing sleep and nocturnal disability in Parkinson's disease. JNeurol Neurosurg Psychiatry 2002; 73:629-35) Hoehn and Yahr staging andSchwab and England ADL scaleshttp://neurosurgery.mgh.harvard.edu/functional/pdstages.htm). Safetyassessments such as mMIDI (Grant J E. Impulse control disorders: Aclinician's guide to understanding and treating behavioral addictions.New York: W.W. Norton & Company; 2008) and C-SSR (Posner et al.Columbia-Suicide Severity Rating Scale. Am J Psychiatry, 2011 168(12)1266-1277) can also be used to establish clinical endpoints.

As noted above, as well as the symptoms of PD described above, PDpatients in the course of their treatment can experience dyskinesia, astate where drug-induced involuntary muscle movements occur. Dyskinesiais not thought to be a symptom of PD itself but instead a side effect ofthe drugs used for the treatment of PD symptoms. Dyskinesia, for exampleresulting from high levels of levodopa, can occur during the ON statewhen the normal PD symptoms are otherwise under control.Levodopa-induced dyskinesia appears in patients who have taken levodopafor a prolonged period of time and generally occurs during the ON statealthough in late stage PD, dyskinesia can occur in OFF state.

Dyskinesia can be categorised into three main types. The most commonform is peak-dose dyskinesia that occurs at peak levodopa levels and canbe ameliorated by reducing the levodopa dose. A second form is diphasicdyskinesia occurring when levodopa levels are rising or falling and canalso be ameliorated by reducing the levodopa dose. A third form ofdyskinesia is OFF-time dystonia, these are sustained muscle contractionsthat cause, for example, twisting and repetitive movements or abnormalpostures. These OFF-time dystonia correlate with akinesia (inability toinitiate movement) when levodopa levels are low and are treatable withlevodopa. A major challenge in the treatment of PD is to improve the PDpatient's ON time (and/or conversely reduce the OFF time) withoutincreasing the dyskinesia associated with PD therapy.

Late stage PD patients, classified as those patients who, after theinitiation of levodopa therapy may i) suffer from an insufficientcontrol of PD symptoms despite treatment with levodopa and/or ii) maysuffer from motor complications such as motor fluctuations (which can bedose dependent or non-dose dependent) and dyskinesia. Delayed-ON is aprolongation of the time required for an anti-Parkinsonian drug effectto appear.

Dose-dependent (or predictable) motor complications are related to thetime of dosing e.g. peak dose dyskinesias, end of dose (or wearing off)deterioration and biphasic dyskinesias. For less predictable motorcomplications (e.g. paroxysmal ON-OFF phenomenon, freezing), therapyintends to reduce the duration and/or intensity of OFF state. Hence, themain efficacy variable can be the decrease in the number, durationand/or intensity of OFF state. It should also be clear to what extentON-time with dyskinesia and ON-time without dyskinesia is increased. Inhighly advanced PD, patients may suffer from severe and highlyunpredictable and rapid motor fluctuations.

Therapies aimed to modify disease progression can either prevent orpostpone late motor complications or fluctuations and/or delay diseaseprogression. Ideally treatment should stop, or substantially reduce,further neurodegeneration and delay disease progression. However themechanisms responsible for the dopaminergic cell loss in PD are unknown.No pharmacotherapy currently exists that has shown a relevant delay indisease progression.

For early untreated PD (de novo) patients a clinical goal to be achievedis to slow the progression of motor symptoms by assessing change inUPDRS.

For stable treated PD patients a clinical goal to be achieved is to slowfurther decline of motor impairment, prevent progression of disability,and prevent motor and non-motor complications. Key outcome measurementsfor this stage could be the emergence of so-called axial symptoms: e.g.freezing of gait, loss of balance or Hoehn and Yahr stage III(“bilateral disease: mild to moderate disability with impaired posturalreflexes; physically independent” or “mild to moderate bilateraldisease; some postural instability; physically independent”).

For patients with advanced PD a clinical goal to be achieved is theprevention of disability. Clinical endpoints in this patent group arewide-ranging and include reductions in autonomic failure or falls,reduction of cognitive symptoms and possibly ‘time to’ dementia and‘time to’ nursing home placement.

Combinations of carbidopa and levodopa are well known in the art,commercial examples of this combination with various releasecharacteristics include Sinemet, Sinemet CR, Duodopa, Apodespan PR andLecado.

Entacapone is a commercially available COMT inhibitor that has beenclinically used in combination with carbidopa and levodopa for thetreatment of PD. Entacapone is, for example, described in PCTpublication nos WO0101984 (A1), WO0015196 (A1), WO2007090923 (A1),WO2006131591 (A2) and WO2011107653 (A2).

Recently, an improved COMT inhibitor termed opicapone(5-[3-(2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol)has been employed in clinical trials together with levodopa and an AADCinhibitor such as carbidopa.

Opicapone is described inter alia in PCT/PT06/000020, PCT/PT2007/000016,PCT/PT2007/000043, PCT/PT2008/000042, PCT/PT2009/000044,PCT/PT2009/000013, PCT/PT2009/000009, PCT/PT2012/000048,PCT/PT2010/000014, PCT/PT2010/000015, PCT/GB2011/052056. Clinical trialsof opicapone are described in Efficacy and Safety of BIA 9-1067 inIdiopathic Parkinson's Disease Patients; Efficacy and Safety of BIA9-1067 in Idiopathic Parkinson's Disease Patients With “Wearing-off”Phenomenon; Pharmacokinetics of BIA 9-1067 and Its Metabolites inHealthy Male Elderly Subjects and in Healthy Male Young Subjects; Effectof Three Multiple-dose Regimens of BIA 9 1067 at Steady-state on theLevodopa Pharmacokinetics; Pharmacokinetic-pharmacodynamic InteractionBetween Three Different Single Doses of BIA 9-1067 and a Single-dose ofImmediate-release Levodopa/Benserazide; Pharmacokinetic-pharmacodynamicInteraction Between Three Different Single Doses of BIA 9-1067 and aSingle-dose of Controlled-release 100/25 mg Levodopa/Benserazide;Pharmacokinetic-pharmacodynamic Interaction Between Each of ThreeDifferent Single Doses of BIA 9-1067 and a Single-dose ofControlled-release 100/25 mg Levodopa/Carbidopa; ComparativeBioavailability Study of BIA 9-1067 25 mg Capsules; Pharmacokinetics ofBIA 9-1067 in Subjects With Hepatic Impairment;Pharmacokinetic-pharmacodynamic Interaction Between Each of ThreeDiferente Single Doses of BIA 9-1067 and a Single-dose ofImmediate-release 100/25 mg Levodopa/Carbidopa; Effect of BIA 9-1067 onthe Pharmacokinetics and Pharmacodynamics of Warfarin; Absorption,Distribution, Metabolism and Excretion of [14C]-Labeled BIA 9-1067 andMetabolites; Tolerability, Pharmacokinetics and Pharmacodynamics of BIA9-1067; Effect of BIA 9-1067 on Rasagiline Pharmacokinetics; Effect ofBIA 9-1067 on the Pharmacokinetics of Repaglinide; Effect of Rasagilineon BIA 9-1067 Pharmacokinetics; Pharmacokinetic Interaction Between BIA9-1067 and Standard-release Levodopa/Carbidopa; Pharmacokinetics of BIA9-1067 in Healthy Japanese and Caucasian Subjects; Effect of BIA 9-1067at Steady-state on the Pharmacokinetics of Levodopa/Carbidopa andLevodopa/Benserazide; Effect of BIA 9-1067 on Cardiac Repolarization inHealthy Adult Men and Women; Study of BIA 9-1067 to Investigate ItsEffect on Levodopa Pharmacokinetic; A Single Oral Ascending Dose Studyof BIA 9-1067 in Healthy Male Subjects; A Study to Investigate theTolerability and Effect of Three Single-dose Regimens of BIA 9-1067; TheEffect of BIA 9-1067 at Steady-state on the Levodopa Pharmacokinetics;An Open-label Study in Healthy Male Subjects to Assess the Absorption,Distribution, Metabolism and Excretion of [14C]-Labelled BIA 9-1067 andMetabolites; Continuation Treatment Protocol for Patient WhoParticipated in the BIA 9-1067-302 Clinical Trial; Multicentre Study inFour Parallel Groups of Parkinson's Disease (PD) Patients. Details ofthese clinical trials can be found at http://clinicaltrials.gov.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the change from baseline in absolute OFF-time as describedin Examples 1A and 1B.

FIG. 2 shows the change from baseline in absolute ON-time withouttroublesome dyskinesia as described in Examples 1A and 1B.

FIG. 3 shows study design of the placebo-controlled double-blind (DB)trial as described in Examples 1A and 1B.

THE INVENTION

FIGS. 1 and 2 disclose the use of opicapone together with levodopa andcarbidopa or benserazide in patients not previously treated with theCOMT inhibitor, opicapone (i.e. naïve to opicapone). When a comparisonis made between patient groups naïve to opicapone and those previouslytreated with opicapone, it was observed that, for the patients treatedwith opicapone from an earlier stage, the PD had progressed less. Whenthe results are analysed, it can be observed that PD had progressedless. The protocols by which patients were treated are provided inExample 1 herein and in the schematic in FIG. 3. The patients weretreated with opicapone once a day. This dose was administered in theevening, at bedtime.

This is the first time that a treatment regimen has been shown to slowthe progression of PD and so provides a significant development intherapy. As used herein slowing the progression of PD also refers toinstances where the progression of PD is delayed by a period of time.For patient treated according to the invention the progression of PD maybe delayed by a period of at least one month relative to patients whohave not received the treatment of the invention, for example by atleast 3 months, at least 4 months, at least 5 months, at least 6 months,at least 7 months, a least 9 months or at least one year.

Accordingly, the present invention provides a method of slowing ordelaying the progression of PD by administering to a patient notpreviously treated with opicapone for at least a period of time beforestarting the administration:

-   -   (i) levodopa;    -   (ii) an AADC inhibitor such as carbidopa or benserazide; and    -   (iii) opicapone.

The present invention also provides the use of opicapone to slow theprogression of PD by administering to a patient not previously treatedwith opicapone for at least a period of time before starting theadministration:

(i) levodopa;

(ii) an AADC inhibitor such as carbidopa or benserazide; and

(iii) opicapone.

Alternative COMT inhibitors (COMTis) include tolcapone and entacapone.

Such period of time may be, for example, for 2 weeks, 1 month, 3 months,6 months, 12 months, 18 months, or 24 months. The patient may never havetaken opicapone before starting the treatment of the present invention.Any of the medicaments set forth above in (i), (ii) and (iii) may bepresent as a pharmaceutically acceptable salt or ester, if desired. Themedicaments may be administered separately (concomitantly orsequentially), or in a fixed dose combination of two or more of (i),(ii) and (iii). When in a fixed-dose combination, the release of one ormore of the medicaments may be modified to provide rapid, sustainedand/or delayed release of one or more of the medicaments. Such rapidrelease forms may be immediate release forms.

The patient to be treated according to the invention may have previouslybeen experiencing a mean daily OFF time of up to 6 hours prior totreatment according to the invention, for example up to 1 hour, up to 2hours, up to 3 hours, up to 4 hours, or up to 5 hours per day. Suchpatients may have had a PD diagnosis for up to 9 years, for example upto 1 month, up to 2 months, up to 3 months, up to 4 months, up to 6months, up to 12 months, up to 2 years, up to 3 years, up to 4 years, upto 5 years, up to 6 years, up to 7 years or up to 8 years. The patientsto be treated according to the invention may have previously beenexperiencing motor symptoms and/or motor complications such as motorfluctuations with or without dyskinesias for up to 4 years prior totreatment according to the invention, for example up to 1 month, up to 2months, up to 3 months, up to 4 months, up to 6 months, up to 12 months,up to 2 years, or up to 3 years. The patients to be treated according tothe invention may have previously been taking an average daily dose oflevodopa of up to 800 mg prior to treatment according to the invention,for example up to 700 mg, up to 600 mg, up to 500 mg, up to 400 mg, upto 300 mg, up to 200 mg, or up to 100 mg. In such patients administeredwith opicapone according to the invention the OFF time will decrease andthe daily dosing of levodopa may decrease, at least initially.

The opicapone may be employed by once a day dosing, for example at 5 mgto 100 mg, more usually 25 mg to 75 mg, for example 50 mg per day.Individual doses of 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg,30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80mg, 85 mg, 90 mg, 95 mg, 100 mg or the like may be employed (or such adose at 10%).

The opicapone may be administered at any time but more suitably not ator near mealtime, and/or more suitably not together with levodopa ornear administration thereof. Particularly aptly the opicapone isadministered in the evening, for example at least an hour before orafter a meal and at least an hour before or after the lastadministration of levodopa, for example before going to bed (atbedtime). Suitable administration is described in PCT/GB2011/052056.

The dosage unit for opicapone may be a tablet, a capsule or the like.Administration is usually and preferably oral.

The opicapone, levodopa and AADC inhibitor (such as carbidopa orbenserazide) will be administered in an amount effective to treatParkinson's disease in a patient in need thereof.

The levodopa and AADC inhibitor will usually be administered at the sametime as each other, for example as a single dosage unit such as atablet. The single dosage may include a fixed dose combination unit.Alternatively, part or all of the AADC inhibitor may be administeredseparately if desired.

The dose of levodopa will normally be from 50 mg to 250 mg, more usuallyfrom 95 mg to 200 mg, for example 100 mg or 150 mg.

The dose of AADC inhibitor may conventionally be in a ratio of 1:4 withlevodopa, for example 25 mg benserazide or carbidopa together with 100mg levodopa. Higher doses of AADC inhibitor may be employed if desired,for example co-formulated with the levodopa although additional dosessuch as tablet(s), for example of 25 mg carbidopa, may be employed.

The levodopa may be administered from, for example, 2 to 10 times a dayin order to minimise the patients symptoms thereby minimising thepatient's end-of-dose wearing off symptoms and “off-time”. Generally 3,4, 5, 6, 7 or 8 times a day is employed, for example 3, 4 or 5 times aday.

When opicapone is used in combination with levodopa and carbidopa, adaily dose of levodopa from 400 mg to 1600 mg and carbidopa from 100 to650 mg can used. In this case the daily dose of levodopa and carbidopais provided in 2 to 10 doses per day, for example, 2, 3, 4, 5, 6, 7, 8,9 or 10 doses a day.

When opicapone is used in combination with levodopa and benserazide, adaily dose of levodopa from 400 mg to 1600 mg and benserazide from 100to 650 mg can be used. In this case the daily dose of levodopa andbenserazide is provided in 2 to 10 doses per day, for example, 2, 3, 4,5, 6, 7, 8, 9 or 10 doses a day.

Use of opicapone with an agent delivering a pharmacologically equivalentdose of levodopa and/or the AADC inhibitors detailed above is alsoenvisaged.

Opicapone may be indicated as adjunctive therapy to preparations oflevodopa/benserazide or levodopa/carbidopa in adult patients withParkinson's disease and motor fluctuations. Use of opicapone for thetreatment of (or method of treating) Parkinson's disease in adultpatients with Parkinson's disease and motor fluctuations in combinationwith preparations of levodopa/benserazide or levodopa/carbidopa istherefore also envisaged.

Opicapone may be indicated as adjunctive therapy to immediate release ormodified release preparations of levodopa/benserazide orlevodopa/carbidopa in adult patients with Parkinson's disease andend-of-dose motor fluctuations who cannot be stabilised on thosecombinations. Use of opicapone for the treatment of (or method oftreating) Parkinson's disease in adult patients with Parkinson's diseaseand end-of-dose motor fluctuations in combination with immediate releaseor modified release preparations of levodopa/benserazide orlevodopa/carbidopa wherein the end-of-dose motor fluctuations cannot bestabilised by the preparations of levodopa/benserazide orlevodopa/carbidopa alone is therefore also envisaged.

Suitable dosages and combinations are described in Table 1:

TABLE 1 Combination of opicapone with levodopa/ AADCi,levodopa/AADCi/COMTi and AADCi preparations. Capsules/Tablets/OtherCombinations Immediate Release (IR)/ Dosage(s) Administration withopicapone Controlled Release (CR) (mg/mg) regime(s) Levodopa/AADCipreparations Levodopa/ IR   50/12.5 400-1600 mg of L- Carbidopa 100/10DOPA and 100/25 carbidopa 100- Orally 250/25 650 mg daily inDisintegrating 100/10 divided doses (2 to 100/25 10 doses per day,250/25 for example, 2, 3, 4, CR 200/50 5, 6, 7, 8, 9 or 10 100/25 dosesa day) Intestinal Gel 20/5 Levodopa/ Capsules/Tablets   50/12.5 400-1600mg of Benserazide 100/25 levodopa and 200/50 benserazide 100- 650 mgdaily in divided doses (2 to 10 doses per day, for example, 2, 3, 4, 5,6, 7, 8, 9 or 10 doses a day)

A particularly apt dosage of levodopa is 100 mg levodopa and 25 mg AADCinhibitor (AADCi) particularly carbidopa.

It is a further advantage of this invention that control of dyskinesiasmay be achieved. This may be due at least in part to the association ofthe use of opicapone administered, for example, once a day, togetherwith a dose of levodopa such as 100 mg.

Favourably the levodopa is present in a rapidly dissolving tabletalthough sustained release forms may be employed. The levodopa may alsobe used in delayed or immediate release forms.

In one suitable embodiment, the treatment is administered to a patientnot previously treated with a COMT inhibitor such as entacapone,tolcapone or opicapone for at least a period of time before starting thetreatment of the present invention. Such period of time may be, forexample, for 2 weeks, 1 month, 3 months, 6 months, 12 months, 18 months,or 24 months. The patient to be treated according to the invention maynever have taken a COMT inhibitor before starting the treatment of thepresent invention. Such patients to be treated according to theinvention may have previously been experiencing a mean daily OFF time ofup to 6 hours prior to treatment according to the invention, for exampleup to 1 hour, up to 2 hours, up to 3 hours, up to 4 hours, or up to 5hours per day. Such patients to be treated according to the inventionmay have had a PD diagnosis for up to 9 years prior to treatmentaccording to the invention, for example up to 1 month, up to 2 months,up to 3 months, up to 4 months, up to 6 months, up to 12 months, up to 2years, up to 3 years, up to 4 years, up to 5 years, up to 6 years, up to7 years or up to 8 years. The patients to be treated according to theinvention may have been experiencing motor symptoms and/or motorcomplications such as motor fluctuations with or without dyskinesias forup to 4 years prior to treatment according to the invention, for exampleup to 1 month, up to 2 months, up to 3 months, up to 4 months, up to 6months, up to 12 months, up to 2 years, or up to 3 years. The patientsto be treated according to the invention may be taking an average dailydose of levodopa of up to 800 mg prior to treatment according to theinvention, for example up to 700 mg, up to 600 mg, up to 500 mg, up to400 mg, up to 300 mg, up to 200 mg, or up to 100 mg.

In another suitable embodiment, there is provided a method of slowingprogression of PD in a patient previously treated with an effective doseof levodopa and an AADC inhibitor which comprises administering aneffective dose of opicapone to said patient. In such cases the AADCinhibitor can be carbidopa or benserazide.

In another suitable embodiment there is opicapone for use delaying theprogression of PD in a patient also treated with levodopa and an AADCinhibitor. In such cases the AADC inhibitor can be carbidopa orbenserazide.

Such patients to be treated according to the invention may have beenexperiencing a mean daily OFF time of up to 6 hours prior to treatmentaccording to the invention, for example up to 1 hour, up to 2 hours, upto 3 hours, up to 4 hours, or up to 5 hours per day. Such patients to betreated according to the invention may have had a PD diagnosis for up to9 years, for example up to 1 month prior to treatment according to theinvention, up to 2 months, up to 3 months, up to 4 months, up to 6months, up to 12 months, up to 2 years, up to 3 years, up to 4 years, upto 5 years, up to 6 years, up to 7 years or up to 8 years. The patientsto be treated according to the invention may have been experiencingmotor symptoms and/or motor complications such as motor fluctuationswith or without dyskinesias for up to 4 years prior to treatmentaccording to the invention, for example up to 1 month, up to 2 months,up to 3 months, up to 4 months, up to 6 months, up to 12 months, up to 2years, or up to 3 years. The patients to be treated according to theinvention may have been taking an average daily dose of levodopa of upto 800 mg prior to treatment according to the invention, for example upto 700 mg, up to 600 mg, up to 500 mg, up to 400 mg, up to 300 mg, up to200 mg, or up to 100 mg.

The opicapone may be employed by once a day dosing, for example at 5 mgto 100 mg, more usually 25 mg to 75 mg, for example 50 mg per day.Individual doses of 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg,30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80mg, 85 mg, 90 mg, 95 mg, 100 mg or the like may be employed (or such adose at 10%).

The opicapone may be administered at any time but more suitably not ator near mealtime, and/or more suitably not together with levodopa ornear administration thereof. Particularly aptly the opicapone isadministered in the evening, for example at least an hour before orafter a meal and at least an hour before or after the lastadministration of levodopa, for example before going to bed (atbedtime). Suitable administration is described in PCT/GB2011/052056.

The dosage unit for opicapone may be a tablet, a capsule or the like.Administration usually and preferably oral.

In another suitable embodiment there is provided a method of slowing ordelaying progression of PD in a patient diagnosed with, but previouslyuntreated for, Parkinson's disease which comprises administering aneffective dose of opicapone to said patient. The invention also providesthe use of opicapone for slowing or delaying progression of PD in apatient diagnosed with, but previously untreated for, Parkinson'sdisease which comprises administering an effective dose of opicapone tosaid patient. For example, use of opicapone in the treatment of thesymptoms of idiopathic PD without or in combination with levodopa, i.e.over the course of the disease, including through to late stages whenthe effect of levodopa wears off or becomes inconsistent andfluctuations of the therapeutic effect occur (end of dose or ON-OFFfluctuations

As described herein a patient previously untreated for PD includes thosePD patients who have not previously taken medication for treatment ofPD. Medication for treatment of PD is described in Table 2 and includesdopamine agonists, dopamine precursors such as levodopa, COMTinhibitors, MAO-B inhibitors, and anti-cholinergics. Before commencingtreatment according to the invention such patients may experience a meandaily OFF time of up to 6 hours, for example up to 1 hour, up to 2hours, up to 3 hours, up to 4 hours, or up to 5 hours per day. Beforecommencing treatment according to the invention such patients may havehad a PD diagnosis for up to 9 years, for example up to 1 month, up to 2months, up to 3 months, up to 4 months, up to 6 months, up to 12 months,up to 2 years, up to 3 years, up to 4 years, up to 5 years, up to 6years, up to 7 years or up to 8 years. Before commencing treatmentaccording to the invention the patients may experience motor symptomsand/or motor complications such as motor fluctuations with or withoutdyskinesias for up to 4 years, for example up to 1 month, up to 2months, up to 3 months, up to 4 months, up to 6 months, up to 12 months,up to 2 years, or up to 3 years.

TABLE 2 Parkinson's Disease Medication Part A Capsules/Tablets/OtherImmediate Release (IR)/ Controlled/Extended Dosage(s) AdministrationDrug Type Release (CR/ER) (mg) regime(s) Dopamine agonists PramipexoleConventional tablets 0.125 mg TID (1.5-4.5 mg daily) 0.25 mg 0.5 mg 0.75mg 1 mg 1.5 mg Extended release 0.375 mg QD (1.5-4.5 mg daily) 0.75 mg1.5 mg 2.25 mg 3 mg 3.75 mg 4.5 mg Ropinirole Conventional tablets 0.25mg TID (2-24 mg daily) 0.5 mg 1 mg 2 mg 3 mg 4 mg 5 mg Extended releasetablets 2 mg QD (2-24 mg daily) 4 mg 6 mg 8 mg 12 mg RotigotineTransdermal system 1 mg QD (2-8 mg daily) 2 mg 3 mg 4 mg 6 mg 8 mgApomorphine Ampoules - Solution for Injection or Infusion BromocriptinePen - Solution for 10 mg/ml 2 mg PRN, up to 20 Injection mg/dayPre-filled Syringe - 5 mg/ml Continuous infusion 12- solution forinfusion 24 h/day Tablets 1 mg TID (5-30 mg daily) 2.5 mg LisurideCapsules 5 mg BID or TID (0.6-5 mg daily) Tablets 10 mg PergolideTablets 0.2 mg TID (0.75-5 mg daily) 0.05 mg 0.25 mg 1 mg CabergolineTablets 0.5 mg QD (2-4 mg daily) Budipine Tablets 10 mg 20 mg 30 mgPiribedil Tablets 20 mg 20 mgTID 50 mg Retard 50 mgQD Talipexole Tablets0.4 mg BID or TID (0.4-3.6 mg daily) Dopamine precursorsLevodopa-carbidopa See Part B See Part B Levodopa- See Part B See Part Bbenserazide Levodopa- See Part B See Part B carbidopa- entacapone COMTinhibitors Entacapone Tablets 200 mg 200 mg up to ten times dailyEntacapone- See Part B See Part B levodopa-carbidopa Tolcapone Tablets100 mg TID 200 mg MAO-B inhibitors Selegiline Tablets/Capsules 5 mg 5 mgBID 10 mg 10 mg QD Syrup 10 mg/5 ml Orally Disintegrating 1.25 mg 1.25QD Tablets Rasagiline Tablets 0.5 mg QD 1 mg Other drugs AmantadineCapsules/Tablets 100 mg 100-400 mg QD Syrup 50 mg/5 ml AnticholinergicsTrihexylphenidyl Tablets 2 mg TID (6-8 mg daily) (benzhexol) 5 mg Elixir 2 mg/5 ml Biperiden Tablets 2 mg 3-16 mg daily in divided 4 mg dosesBenztropine Tablets 0.5 mg 4-6 mg daily in divided 1 mg doses 2 mgInjection IM IV 2 mg/ml Procyclidine Tablets 5 mg 2.5-5 mg TIDOrphenadrine Injection IM 30 mg/ml 60 mg BID Part BCapsules/Tablets/Other Immediate Release (IR)/ Dosage(s) AdministrationCombinations Controlled Release (CR) (mg) regime(s) Levodopa/AADCiLevodopa-Carbidopa IR   50/12.5 400-1600 mg of levodopa 100/10 individed doses 100/25 250/25 Orally Disintegrating 100/10 100/25 250/25CR 200/50 100/25 Intestinal Gel 20/5 Levodopa-BenserazideCapsules/Tablets   50/12.5 100/25 200/50 Dispersible Tablets   50/12.5100/25 Controlled release 100/25 Levodopa/AADCi/ COMTiLevodopa-carbidopa- 50/12.5/200 Entacapone 75/18.75/200 100/25/200125/31.25/200 150/37.5/200 200/50/200 TID—three times per day BID—twiceper day QD—once per day

The patient to be treated for Parkinson's disease may have beenpreviously treated with L-DOPA. The patient to be treated forParkinson's disease may not have been previously treated with L-DOPA.The patient to be treated for Parkinson's disease may have beenpreviously treated with a dopamine agonist or MAO-B inhibitor such asset out above. The patient to be treated for Parkinson's disease may nothave been previously treated with a dopamine agonist or MAO-B inhibitor.The patient to be treated for Parkinson's disease may not have beenpreviously treated for Parkinson's disease.

In another suitable embodiment the treatment according to the inventionis administered to a patient not previously treated with levodopa for atleast a period of time before starting the treatment of the presentinvention. Such period of time may be, for example, for 2 weeks, 1month, 3 months, 6 months, 12 months, 18 months, or 24 months. Thepatient to be treated according to the invention may never have takenlevodopa before starting the treatment of the present invention.

The opicapone may be employed by once a day dosing, for example at 5 mgto 100 mg, more usually 25 mg to 75 mg, for example 50 mg per day.Individual doses of 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg,30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80mg, 85 mg, 90 mg, 95 mg, 100 mg or the like may be employed (or such adose at 10%).

The opicapone may be administered at any time but more suitably not ator near mealtime, and/or more suitably not together with levodopa ornear administration thereof. Particularly aptly the opicapone isadministered in the evening, for example at least an hour before orafter a meal and at least an hour before or after the lastadministration of levodopa, for example before going to bed (atbedtime). Suitable administration is described in PCT/GB2011/052056.

The dosage unit for opicapone may be a tablet, a capsule or the like.Administration is usually and preferably oral.

The progression of Parkinson's Disease may be determined by noting thechange in any PD symptom or commonly used measure of PD symptoms (seeExamples 1A and 1B), for example, OFF time and/or ON time, for example areduction in OFF time compared to starting the treatment of theinvention and/or an increase in ON time compared to starting thetreatment of the invention. The reduction in OFF time could suitably beof at least 10 minutes. The reduction in OFF time by at least 10 minutescan be for example at least 15 minutes, at least 30 minutes, at least 45minutes or at least an hour, for example between 15 minutes and 30minutes, between 30 minutes and an hour. A corresponding relativeimprovement in ON time may similarly be employed to determineprogression of disease. As shown in FIG. 1, at least 12 months postcommencement of treatment with opicapone, a difference of approximately−2.0 hrs in OFF time is seen. As shown in FIG. 2, at least 12 monthspost commencement of treatment with opicapone a difference ofapproximately +1.5 hr in ON time without troublesome dyskinesia is seen.

Example 1A

After completion of the placebo-controlled double-blind (DB) trial—seeFIG. 3, 367 (97.6%) patients continued to a 1-year open label (OL)-part,in which all subjects were treated with OPC (25 or 50-mg OPC). Allsubjects began with 25-mg OPC once daily (QD) for 1-week. Then, theinvestigator freely adjusted the levodopa therapy and/or OPC based onthe dopaminergic response and/or associated adverse events. Efficacyvariables included the change from baseline in OFF/ON-time, based onpatient diaries. Other endpoints include proportion of responders.UPDRS, PD questionnaire (PDQ-39), Non-Motor Symptom Scale (NMSS), PDSleep Scale (PDSS) and safety assessments (including Columbia SuicideSeverity Rating Scale (C-SSRS). Modified Minnesota Impulsive DisordersInterview (mMIDI)) was also employed.

Example 1B

After completion of the placebo-controlled double-blind (DB) trial—seeFIG. 3, 495 (92%) patients continued to a 1-year open label (OL)-part,in which all subjects were treated with OPC (5, 25 or 50-mg OPC). Allsubjects began with 25-mg OPC QD for 1-week. Then, the investigatorfreely adjusted the levodopa therapy and/or OPC based on thedopaminergic response and/or associated adverse events. Efficacyvariables included the change from baseline in OFF/ON-time, based onpatient diaries. Other endpoints include proportion of responders.UPDRS, PDQ-39, NMSS, PDSS and safety assessments (including C—SSRS andmMIDI).

The data from the trials is shown in FIGS. 1 and 2.

The demographic details of the patients at baseline of the double blindportion of the study in Example 1A is presented in Table 3 below. Thedemographic details of the patients at baseline of the open labelextension period of the study in Example 1A is presented in Table 4.

TABLE 3 Demographic details of PD patients on entry to the double blindstudy of Example 1A. Placebo 25 mg OPC 50 mg OPC (N = 120) (N = 116) (N= 115) Age (yrs) Mean (SD) 61.5 (8.9) 62.5 (8.5) 65.5 (8.4) Gender Malen (%) 71 (52.6) 82 (65.6) 89 (60.5) Female n (%) 64 (47.4) 43 (34.4) 58(39.5) Race Asian n (%) 42 (31.1) 29 (23.2) 31 (21.1) Caucasian n (%) 89(65.9) 90 (72.0) 115 (78.2) Neither Asian or caucasian n (%) 3 (2.2) 6(4.8) 1 (0.7) Weight (kg) Mean (SD) 72 (7.0) 75 (16.8) 72 (15.1) BodyMass Index (kg/m²) Mean (SD) 27 (5.2) 27 (4.9) 26 (4.3) Time since: PDdiagnosis (yrs) Mean (SD) 7.7 (3.7) 8.5 (4.4) 8.2 (4.6) Motorfluctuations (yrs) Mean (SD) 3.6 (2.7) 3.8 (2.8) 3.6 (3.5) L-DOPAtreatment (yrs) Mean (SD) 6.7 (3.6) 7.1 (4.2) 7.0 (4.7) OFF-time (hrs)Mean (SD) 6.1 (2.3) 6.2 (2.2) 6.3 (2.2) L-DOPA Daily-dose (mg) Mean (SD)714 (337.5) 806 (398.2) 700 (311.9)

TABLE 4 Demographic details of opicapone (OPC) treated PD Patients onentry to the open label extension period of the study of Example 1A. OPCCharacteristic Statistic (N = 339) Age (years) Mean (SD) 63 (9) GenderMale n (%) 201 (59.3%) Female n (%) 138 (40.7%) Race Asian n (%) 238(70.2%) Caucasian n (%) 91 (26.8%) Neither Asian nor Caucasian n (%) 10(2.9%) Levodopa daily dose (mg) Mean (SD) 707.3 (334.3) OFF-time (hours)Mean (SD) 4.5 (3.0) SD = standard deviation

The demographic details of the patients at baseline of the double blindportion of the study in Example 1B is presented in Table 5 below. Thedemographic details of the patients at baseline of the open labelextension period of the study in Example 1B is presented in Table 6.

TABLE 5 Demographic details of PD patients on entry to the double blindstudy of Example 1B. Placebo Entacapone 5 mg OPC 25 mg OPC 50 mg OPC (N= 121) (N = 122) (N = 122) (N = 119) (N = 115) Age (yrs) Mean (SD) 64(9.3) 64 (8.8) 64 (9.3) 64 (8.9) 64 (9.2) Gender Male n (%) 71 (58.7%)76 (62.3%) 71 (58.2%) 67 (56.3%) 69 (60.0%) Female n (%) 50 (41.3%) 46(37.7%) 51 (41.8%) 52 (43.7%) 46 (40.0%) Race Caucasian n (%) 121 (100)122 (100) 122 (100) 119 (100) 115 (100) Weight (kg) Mean (SD) 76 (13.3)77 (15.0) 75 (12.0) 76 (14.1) 76 (14.5) Body Mass Index (kg/m²) Mean(SD) 27 (4.3) 27 (4.6) 26 (4.5) 27 (4.3) 27 (4.6) Time since: PDdiagnosis (yrs) Mean (SD) 7.7 (4.2) 7.1 (4.1) 7.5 (3.6) 7.2 (4.1) 7.0(3.8) Motor fluctuations (yrs) Mean (SD) 2.2 (1.9) 2.2 (2.1) 2.3 (2.3)2.3 (2.5) 2.2 (2.3) L-DOPA treatment (yrs) Mean (SD) 5.8 (3.7) 5.6 (4.1)5.8 (3.5) 5.9 (3.9) 5.3 (3.8) OFF-time (hrs) Mean (SD) 6.2 (1.8) 6.5(2.2) 6.7 (2.1) 6.9 (2.2) 6.2 (1.8) L-DOPA Daily-dose (mg) Mean (SD) 675(302.1) 645 (329.7) 642 (310.3) 654 (324.3) 695 (337.5) SD = standarddeviation

TABLE 6 Demographic details of opicapone (OPC) treated PD Patients onentry to the open label extension period of the study of Example 1B. OPCCharacteristic Statistic (N = 339) Age (years) Mean (SD) 64 (9) GenderMale n (%) 298 (60.3%) Female n (%) 196 (39.7%) Race Caucasian n (%) 494(100%) Levodopa daily dose (mg) Mean (SD) 649.4 (307.5) OFF-time (hours)Mean (SD) 4.9 (2.6) SD = standard deviation

Example 2 Introduction:

Opicapone (OPC) was developed to fulfil the need for more potent, saferand longer acting COMT inhibitors.

Objectives:

To investigate the effect of a once-daily (QD) OPC (25, 50 and 75 mg) onlevodopa pharmacokinetics (PK), in comparison to placebo and 200 mgentacapone (ENT).

Methods:

This was a single-centre, double-blind, randomized andplacebo-controlled study in 4-groups of 20 (10 male and 10 female)subjects each. The study consisted of QD administration of OPC orplacebo for 11 days followed by thrice-daily (every 5 h) 100/25 mglevodopa/carbidopa (LC), 200 mg ENT or placebo on Day 12.

Results:

Levodopa extent of exposure (AUC) was significantly increased up to78.9% and 73.7% with 75 mg-OPC in comparison to placebo and ENT,respectively. Levodopa-AUCO-24 was higher when LC was administered withany OPC dose than when administered concomitantly with ENT. Peakexposure (Cmax) to levodopa increased (>30%) with 75 mg-OPC following LCadministrations. A significantly long-lasting and sustained S-COMTinhibition occurred with OPC. Maximum S-COMT inhibition ranged from67.1% (200 mg-ENT) to 94.2% (75 mg-OPC) and was higher than ENT for allOPC doses. The 50 and 75 mg-OPC were somehow similar (75 mg was slightlysuperior); thus, the 75 mg-OPC may not bring a significant advantage to50 mg-OPC with regard to S-COMT inhibition. The tolerability profile ofOPC was favourable.

1-6. (canceled)
 7. A method of slowing progression of Parkinson'sDisease which method comprises administering to a patient not previouslytreated for Parkinson's Disease an effective amount of: (i) levodopa;(ii) an AADC inhibitor; and (iii) opicapone. 8-9. (canceled)
 10. Themethod of claim 7, wherein the slowing of the progression of Parkinson'sDisease involves a delay in the progression of Parkinson's Disease by aperiod of at least one month.
 11. (canceled)
 12. The method of claim 7,wherein opicapone is administered once a day and levodopa isadministered from 2 to 10 times a day.
 13. A method as claimed in claim12, wherein levodopa is administered 3, 4, 5 or 6 times a day.
 14. Themethod of claim 7, wherein the dose of opicapone is 25 mg to 100 mg. 15.The method of claim 7, wherein the AADC inhibitor is carbidopa orbenserazide.
 16. The method of claim 7, wherein the levodopa is presentin a unit dose of from 50 mg to 250 mg.
 17. The method of claim 7,wherein the levodopa is present in a tablet at 100 mg.
 18. The method ofclaim 7, wherein the AADC inhibitor is carbidopa or benserazide, whereinthe levodopa and the AADC inhibitor are present in a single dosage unit.19. The method of claim 18, wherein the single dosage unit is a tabletcomprising 100 mg levodopa and 25 mg carbidopa for use 3, 4, 5 or 6times a day and opicapone 50 mg for use once a day.
 20. (canceled) 21.The method of claim 7, wherein the patient benefits by more than 0.25 hrin OFF period.
 22. A method of delaying progression of Parkinson'sDisease in patients treated with an effective dose of levodopa and anAADC inhibitor which comprises administering an effective dose ofopicapone to said patient, wherein the patient has not been previouslytreated for Parkinson's disease.
 23. (canceled)
 24. The method of claim22, wherein opicapone is administered once a day, wherein the dose ofopicapone is 25 mg to 100 mg.
 25. The method of claim 24, wherein thedose of opicapone is 50 mg.
 26. The method of claim 22, wherein levodopais administered 3, 4, 5 or 6 times a day, wherein levodopa is present ina unit dose of from 50 mg to 250 mg.
 27. The method of claim 22, whereinthe AADC is carbidopa or benserazide in a ratio of 1:4 with levodopa.28. The method of claim 26, wherein levodopa is used at 100 mg andcarbidopa at 25 mg. 29-41. (canceled)